A Phase IB/II Multi-arm Study With Venetoclax in Combination with
Cobimetinib and Venetoclax in Combination with Idasanutlin in Patients
Aged >/= 60 years with Relapsed or Refractory Acute Myeloid Leukemia
Who Are Not Eligible for Cytotoxic Therapy

There are 2 parts to this clinical research study: Phase 1b and Phase
2. The goal of Phase 1b of this study is to find the highest tolerable
dose of venetoclax that can be given in combination with either
cobimetinib or idasanutlin to patients with AML. The goal of Phase 2
of this study is to learn if the study drug combinations can help to
control the disease. The safety of the drug combinations will be
studied in both parts.

Primary Objectives The primary objectives for the Phase Ib portion of
this study are as follows: To assess the safety and tolerability of
venetoclax in combination with cobimetinib, and venetoclax in
combination with idasanutlin To determine the maximum tolerated doses
(MTDs) of venetoclax in combination with cobimetinib, and venetoclax in
combination with idasanutlin To determine the recommended Phase II dose
(RP2D) of the combination of venetoclax with cobimetinib, and the
combination of venetoclax with idasanutlin The primary objective for
the Phase II portion of this study is as follows: To evaluate
preliminary efficacy as measured by the proportion of complete remission
(CR), complete remission with incomplete blood count recovery (CRi), and
complete remission with incomplete platelet count recovery (CRp) with
venetoclax in combination with cobimetinib, and venetoclax in
combination with idasanutlin Secondary Objectives Secondary Efficacy
Objectives The secondary objective for the Phase Ib part of this study
is as follows: To evaluate preliminary efficacy as measured by the
proportion of CR, CRi, and CRp with venetoclax in combination with
cobimetinib, and venetoclax in combination with idasanutlin. The
secondary efficacy objectives for the Phase Ib and II parts of this
study are as follows: Overall Response Rate (ORR) (CR + CRi + CRp +
partial remission/response [PR]) Duration of response (DOR) Time to
progression (TTP) Progression-free survival (PFS) Event-free survival
(EFS) Leukemia-free survival (LFS) Overall survival (OS) Safety
Objectives The safety objective for the Phase II portion of this study
is as follows: To evaluate safety and tolerability of venetoclax in
combination with cobimetinib and of venetoclax in combination with
idasanutlin. Pharmacokinetic Objective The PK objectives for this study
in AML patients are as follows: To characterize the pharmacokinetics
(PK) of venetoclax and cobimetinib when given in combination and to
assess potential pharmacokinetics drug-drug interaction (DDIs) between
venetoclax and cobimetinib To characterize the pharmacokinetics of
venetoclax and idasanutlin (and its M4 metabolite, when appropriate)
when given in combination and to assess potential PK DDIs between
venetoclax and idasanutlin Patient-Reported Outcome Objective The
patient-reported outcome (PRO) objective for this study is as follows:
To evaluate treatment-related tolerability in patients treated with
venetoclax in combination with cobimetinib, and venetoclax in
combination with idasanutlin from the patient perspective

1) Signed Informed Consent Form
2) Age >/= 60 years
3) Able to comply with the study protocol, in the investigator’s judgment
4) Relapsed or refractory AML after prior anti-leukemic therapy by WHO
Classification or patients with prior antecedent hematologic disorders,
such as MDS or CMML, who have received therapy for AHD and have
transformed to AML.
5) Not eligible for cytotoxic therapies
6) Ineligible for allogeneic stem cell transplant
7) Life expectancy of at least 12 weeks
8) ECOG Performance Status 0 - 2
9) Adequate renal function as demonstrated by a calculated creatinine
clearance of >/= 40 mL/min; determined via urine collection for
24-hour creatinine clearance or by the Cockcroft-Gault formula
10) Adequate liver function as demonstrated by (unless abnormal
laboratory values are due to leukemic involvement): Aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) </= 2.5 ×
upper limit of normal (ULN) (or </= 5 × ULN if infiltration of liver
is due to leukemic involvement); total bilirubin </= 1.5 × ULN.
Patients with known Gilbert’s disease who have serum bilirubin </= 3
× ULN may be enrolled.
11) For women of childbearing potential: agreement to remain abstinent
(refrain from heterosexual intercourse) or use contraceptive methods
that result in a failure rate of < 1% per year, during the treatment
period and for at least 3 months after the last dose of study treatment.
A woman is considered to be of childbearing potential if she is
postmenarcheal, has not reached a postmenopausal state (>/= 12
continuous months of amenorrhea with no identified cause other than
menopause), and has not undergone surgical sterilization (removal of
ovaries and/or uterus). Examples of contraceptive methods with a failure
rate of < 1% per year include bilateral tubal ligation, male
sterilization, established proper use of hormonal contraceptives that
inhibit ovulation, hormone-releasing intrauterine devices, and copper
intrauterine devices.
12) continued from #11: Hormonal contraceptive methods must be
supplemented by a barrier method plus spermicide. – The reliability of
sexual abstinence should be evaluated in relation to the duration of the
clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of contraception.
13) For men: agreement to remain abstinent (refrain from heterosexual
intercourse) or use contraceptive measures, and agreement to refrain
from donating sperm, as defined below: With female partners of
childbearing potential, men must remain abstinent or use a condom plus
an additional contraceptive method that together result in a failure
rate of < 1% per year during the treatment period and for at least 3
months after the last dose of study treatment. Men must refrain from
donating sperm during this same period; with pregnant female partners,
men must remain abstinent or use a condom during the treatment period
and for at 3 months after the last dose of study treatment to avoid
exposing the embryo; the reliability of sexual abstinence should be
evaluated in relation to the duration of the clinical trial and the
preferred and usual lifestyle of the patient.
14) continued from #13: Periodic abstinence (e.g., calendar, ovulation,
symptothermal, or postovulation methods) and withdrawal are not
acceptable methods of contraception.

Exclusion:

1) Patients with acute promyelocytic leukemia (French-American-British
[FAB] class M3 AML)
2) Known active CNS involvement with AML at study entry
3) Pregnant or lactating, or intending to become pregnant during the
study. Women of childbearing potential must have a negative serum
pregnancy test result within 14 days prior to initiation of study drug.
4) Treatment with anti-cancer therapy, including chemotherapy or
radiotherapy, or any investigational therapy within 14 days or 5
half-lives, whichever is shorter, prior to initiation of study treatment
with the exception of hydroxyurea
5) Treatment with monoclonal antibodies or antibody drug conjugates for
anti-neoplastic intent within 30 days prior to initiation of study treatment
6) Prior exposure to Bcl-2 inhibitors, MDM2 antagonists or prior
exposure to experimental treatment targeting Raf, MEK, or the MAPK pathway
7) Positive for hepatitis C virus (HCV) antibody at screening unless HCV
RNA is negative
8) Positive for hepatitis B surface antigen (HBsAg) at screening
9) Known history of HIV seropositive status. For patients with unknown
HIV status, HIV testing will be performed at screening if required by
local regulations
10) Any serious medical condition or abnormality in clinical laboratory
tests that, in the investigator’s judgment, precludes the patient’s safe
participation in and completion of the study
11) Malabsorption syndrome or other condition that would interfere with
enteral absorption
12) Planned major surgery during the study
13) Received strong CYP3A inhibitors (such as ketoconazole and
clarithromycin), moderate CYP3A inhibitors (such as fluconazole,
ciprofloxacin, and verapamil) strong CYP3A inducers (such as
carbamazepine and phenytoin), and moderate CYP3A inducers (such as
efavirenz, modafinil) within 7 days prior to the initiation of study treatment
14) Consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or starfruit within 3 days prior
to the initiation of study treatment
15) Received steroid therapy for anti-neoplastic intent
16) Significant cardiovascular disease, such as New York Heart
Association Class >/= 2
17) Patients with an active or uncontrolled infection who are on
anti-microbial agents for treatment of an active infection. Patients
receiving an anti-microbial agent may be eligible if the patient remains
afebrile and hemodynamically stable for 72 hours
18) Patients with active GI conditions (e.g., Grade >/=2
graft-versus-host disease) and uncontrolled inflammatory bowels disease
(i.e., Crohn’s disease, ulcerative colitis, diverticulosis-associated
colitis and Behcet’s disease)
19) History of symptomatic Clostridium difficile infection that required
treatment within 1 month prior to dosing
20) History of other malignancies within 2 years prior to screening,
with the exception of: Adequately treated carcinoma in situ of the
breast or cervix uteri; Basal cell carcinoma of the skin or localized
squamous cell carcinoma of the skin; Low-grade, early-stage prostate
cancer with no requirement for therapy; Previous malignancy confined and
surgically resected (or treated with other modalities) with curative intent
21) White blood cell count > 25 × 10^9/L. Note: hydroxyurea is
permitted to meet this criterion.
22) Patients who might refuse to receive blood products and/or have a
hypersensitivity to blood products
23) Patients with clinically significant persistent electrolyte
abnormalities such as hypokalemia, hyperkalemia, hypocalcemia,
hypercalcemia, hypomagnesemia, and hypermagnesemia of Grade > 1 per
NCI CTCAE, v4.0. Treatment for correction of above electrolyte
imbalances is permitted during screening to meet eligibility.
24) Additional Exclusion Criteria for Phase Ib Dose Escalation Arm A
(Venetoclax and Cobimetinib)-- History or evidence of retinal pathology
on ophthalmologic examination that is considered a risk factor for
neurosensory retinal detachment/central serous chorioretinopathy (CSCR),
retinal vein occlusion (RVO), or neovascular macular degeneration.
Patients will be excluded if they currently have any of the following
risk factors for RVO: Uncontrolled glaucoma with intraocular pressure
> 21mmHg; Serum cholesterol >/= Grade 2; Hypertriglyceridemia
>/= Grade 2; Fasting hyperglycemia >/= Grade 2
25) LVEF below institutional lower limit of normal (LLN) or below 50%,
whichever is lower
26) Additional Exclusion Criteria for Phase Ib Dose-Escalation Arm B
(Venetoclax and Idasanutlin)-- Received the following within 7 days
prior to the initiation of study treatment: Strong CYP2C8 inhibitors or
CYP2C8 substrates; OATP1B1/3 substrates
27) Received the following within 14 days prior to the initiation of
study treatment: Strong CYP2C8 inducers
28) History of liver cirrhosis by radiologic, clinical or laboratory
data, or biopsy despite normal liver function tests
29) Additional Exclusion Criteria for Phase II Expansion Arm A and Arm
B--Received the following within 7 days prior to the initiation of study
treatment: Strong CYP2C8 inhibitors or CYP2C8 substrates; OATP1B1/3 substrates
30) Received the following within 14 days prior to the initiation of
study treatment: Strong CYP2C8 inducers
31) History or evidence of retinal pathology on ophthalmologic
examination that is considered a risk factor for neurosensory retinal
detachment/CSCR, RVO, or neovascular macular degeneration. Patients will
be excluded if they currently have any of the following risk factors for
RVO: Uncontrolled glaucoma with intraocular pressure > 21mmHg; Serum
cholesterol >/= Grade 2; Hypertriglyceridemia >/= Grade 2; Fasting
hyperglycemia >/= Grade 2
32) LVEF below institutional LLN or below 50%, whichever is lower
33) History of liver cirrhosis by radiologic, clinical or laboratory
data, or biopsy despite normal liver function tests